Maternal control of the Drosophila embryonic Dorsal-Ventral axis

果蝇胚胎背腹轴的母体控制

• 批准号: 7891361
• 负责人: DAVID S. STEIN
• 金额: $ 27.19万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891361
• 关键词: Amino Acid Sequence; Area; Blood Clot; Blood coagulation; Cause of Death; Cells; Cleaved cell; Data; Dependence; Development; Disease; Dorsal; Dorsal-Ventral Pattern Formation; Drosophila genus; Embryo; Environment; Etiology; Event; Exhibits; Female; Fibrinolysis; Gene Expression; Generations; Genes; Genetic; Genetic Screening; Glycolipids; Glycoproteins; Glycosaminoglycans; Goals; Health; Human; Human Resources; Inorganic Sulfates; Institutes; Invaded; Knowledge; Laboratories; Lead; Ligands; Membrane; Microscopy; Mission; Modeling; Molecular; Molecular and Cellular Biology; Mutation; Myocardial Infarction; Oogenesis; Pathway interactions; Pattern; Peptide Hydrolases; Perivitelline Space; Physiological Processes; Process; Production; Protein Isoforms; Proteins; Regulation; Research; Research Personnel; Resources; Role; Serine; Serine Protease; Side; Site; Spatial Distribution; Specificity; Stroke; Testing; Texas; Therapeutic Agents; United States National Institutes of Health; Universities; Unspecified or Sulfate Ion Sulfates; Work; base; burden of illness; complement pathway; design; egg; experience; graduate student; improved; insight; microorganism; mutant; protein protein interaction; receptor; research study; sulfation; sulfotransferase

DESCRIPTION (provided by applicant): Dorsal-ventral polarity in the Drosophila embryo is initiated during oogenesis by expression of the Pipe sulfotransferase in the ventral follicle cells which, by an unknown mechanism, leads to the localized activation of a serine protease cascade in the perivitelline space between the embryonic membrane and the eggshell. Our long-term goal is to understand how this serine protease cascade is spatially regulated. The objectives of this application are to elucidate the mechanism through which spatial restriction of the serine protease cascade is implemented and to identify the target of Pipe action in the follicle cell layer. Our central hypothesis is that Pipe activity in the ventral follicle cells results in the sulfation of a glycoprotein or glycolipid that is secreted into and localized within the ventral perivitelline space where it brings about the localized activation of the serine protease cascade. The rationale for the proposed research is that it will greatly expand our understanding of DV pattern formation and will also provide insight into mechanisms that regulate analogous localized serine proteolytic events that influence human health such as the ones involved in the formation and breakdown of blood clots. Blood coagulation and fibrinolysis are critical factors in the etiology of thrombotic diseases such as heart attack and stroke which represent leading causes of death worldwide. Thus, the proposed research is relevant to the mission of the NIH to obtain fundamental knowledge that will potentially reduce the burden of disease. We will pursue two Specific Aims: 1) To determine the extent to which the activity of the serine protease cascade is regulated by the localization of the proteases themselves, by their spatially restricted activation or activities, or by physical interactions with one another that modulate their activities. Functional, tagged versions of the proteases will be used to examine their processing and spatial distribution and to investigate protein-protein interactions in wildtype and various genetic backgrounds. 2) To identify genes involved in the synthesis of the target of Pipe sulfotransferase activity in the ventral follicle cells. Genetic screens will be carried out to identify mutations that lead to the production of dorsalized embryos by mutant females. The proposed research is significant as it will yield new insights into mechanisms that regulate serine protease action and thus may contribute to the development of improved therapeutic agents for the modulation of serine proteases that influence human health.

描述（由申请人提供）：果蝇胚胎中的背腹地极性是在卵子发生过程中通过在腹侧卵泡细胞中表达卵子硫代硫代酶在卵子发生过程中启动的，该腹部卵泡细胞通过未知机制，导致胚胎膜膜和胚膜之间的丝氨酸蛋白酶级联的局部化激活。我们的长期目标是了解这种丝氨酸蛋白酶级联反应如何在空间上调节。该应用程序的目标是阐明实施丝氨酸蛋白酶级联反应并确定卵泡细胞层中管道作用的目标的机制。我们的中心假设是，腹侧卵泡细胞中的管道活性导致糖蛋白或糖脂的硫酸化，该糖蛋白或糖脂被分泌到腹膜周期空间内并将其定位在丝氨酸蛋白酶级联反应的局部激活中。拟议的研究的理由是，它将大大扩展我们对DV模式形成的理解，还将提供对调节类似局部丝氨酸蛋白水解事件的机制的见解，这些机制会影响人类健康，例如参与血液群的形成和分解的机制。血液凝结和纤维蛋白溶解是血栓形成疾病（例如心脏病发作和中风）病因的关键因素，这些因素代表了全世界死亡的主要原因。因此，拟议的研究与NIH的使命有关，以获得可能减轻疾病负担的基本知识。我们将追求两个具体的目标：1）确定丝氨酸蛋白酶级联反应的活动程度，通过蛋白酶本身的定位，通过空间限制的激活或活动来调节丝氨酸蛋白酶的活动，或者通过调节其活动的彼此的身体相互作用。蛋白酶的功能性标记版本将用于检查其处理和空间分布，并研究野生型和各种遗传背景中的蛋白质 - 蛋白质相互作用。 2）鉴定与腹侧卵泡细胞中管道硫代转移酶活性合成的基因。将进行遗传筛选，以识别突变女性导致背胚产生的突变。拟议的研究非常重要，因为它将对调节丝氨酸蛋白酶作用的机制产生新的见解，因此可能有助于改善治疗剂的发展，以调节影响人类健康的丝氨酸蛋白酶。